1. Technical Field
The invention relates to the field of oral medicament administration. In particular, embodiments of the invention concern oral formulations of pharmaceutically useful compositions, for example, N-methylol transfer agents (methylol donating compounds) such as Taurolidine and Taurultam.
2. Description of the Background Art
Taurolidine, Taurultam, N-methylol taurinamide and the like are antineoplastic and antimicrobial compounds that do not exhibit the phenomenon of resistance due to their mechanism of action, which involves a cross-linking reaction with the cell wall of bacteria and with tumor cells. It is known that solutions containing Taurolidine or Taurultam can be used successfully intra-operatively and post-operatively in oncological surgery for intravenous delivery or instillation into a body cavity, for example. In these known methods, as for many pharmaceutical treatment methods, it is important to bring sufficiently high concentrations of the drug (for example, Taurolidine, Taurultam, N-methylol-taurultam and the like) into direct contact with the cells to be treated, such as tumor cells or bacteria, over a long enough time period. For Taurolidine when used for bacterial infection or oncological treatment, concentrations at or near bacteria or the tumor cells preferably should be within a range of from about 2 μg/mL to about 80 μg/mL. In general, higher amounts within this range are required to kill tumor cells by apoptosis without necrosis. Lower levels of the N-methylol transfer agents within this range generally are sufficient to inhibit angiogenesis and tubulogenesis by inhibition of vascular endothelial growth factor (VEGF). This constrains up-growth of new blood vessels and uncontrolled growth of the tumor. Because of the need for relatively high concentrations of N-methylol transfer agent in the blood, serum or plasma and the very poor aqueous solubility of Taurolidine and Taurultam, isotonic solutions of Taurolidine (0.5% to 2.0%) in Ringer's solution usually are administered locally by instillation during surgery in large volumes.
Large amounts of solution also are administered intravenously via a central line or port drips in daily dosages of 4 times 250 mL 2% solution. In routine clinical use for cancer or for infection by bacteria or other infectious agents, these administrations should be delivered for several continuous days, however for practical reasons it is difficult to administer intravenous infusions of this type in the hospital for more than 14 days. Difficulties also may arise due to the large volumes of Taurolidine solution required for infusion, lack of electrolytes, etc. Administration at home is possible, but only in limited circumstances or exceptional cases because of the complex treatment procedure and the high risk of catheter sepsis. Therefore, the use of N-methylol transfer agents in cancer treatment or for treatment of microbial infections, while useful, has certain drawbacks.
There continues to be a need for new formulations that allow oral treatment of neoplastic, infectious and other diseases in which oral dosing can provide adequate blood concentrations of the compound for effective treatment, without the need for long-term intravenous infusion, with its dangers and inconveniences, or other more invasive administration methods.